CARASIL syndrome

Summary

CARASIL syndrome (MONDO:0010829) is a disease caused by HTRA1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: HTRA1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 34
• Phenotypes (HPO): 32

Clinical features

Signs & symptoms

Clinical features (HPO)

32 HPO clinical features (Orphanet curated; top 32 by frequency):

HPO ID	Term	Frequency
HP:0000708	Atypical behavior	Frequent (30-79%)
HP:0001257	Spasticity	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0002401	Stroke-like episode	Frequent (30-79%)
HP:0002497	Spastic ataxia	Frequent (30-79%)
HP:0002634	Arteriosclerosis	Frequent (30-79%)
HP:0003418	Back pain	Frequent (30-79%)
HP:0007024	Pseudobulbar paralysis	Frequent (30-79%)
HP:0008480	Cervical spondylosis	Frequent (30-79%)
HP:0012514	Lower limb pain	Frequent (30-79%)
HP:0030892	Deep cerebral white matter hyperdensities	Frequent (30-79%)
HP:0040161	Localized osteoporosis	Frequent (30-79%)
HP:0100543	Cognitive impairment	Frequent (30-79%)
HP:0000712	Emotional lability	Occasional (5-29%)
HP:0000718	Aggressive behavior	Occasional (5-29%)
HP:0000726	Dementia	Occasional (5-29%)
HP:0000737	Irritability	Occasional (5-29%)
HP:0000741	Apathy	Occasional (5-29%)
HP:0001268	Mental deterioration	Occasional (5-29%)
HP:0001269	Hemiparesis	Occasional (5-29%)
HP:0001297	Stroke	Occasional (5-29%)
HP:0002063	Rigidity	Occasional (5-29%)
HP:0002293	Alopecia of scalp	Occasional (5-29%)
HP:0002506	Diffuse cerebral atrophy	Occasional (5-29%)
HP:0003474	Somatic sensory dysfunction	Occasional (5-29%)
HP:0007256	Abnormal pyramidal sign	Occasional (5-29%)
HP:0012671	Abulia	Occasional (5-29%)
HP:0012672	Akinetic mutism	Occasional (5-29%)
HP:0030833	Neck pain	Occasional (5-29%)
HP:0003657	Granular osmiophilic deposits (GROD) in cells	Excluded (0%)
HP:0002069	Bilateral tonic-clonic seizure	Very rare (<1-4%)
HP:0002751	Kyphoscoliosis	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	CARASIL syndrome
Mondo ID	MONDO:0010829
MeSH	C563990
OMIM	600142
Orphanet	199354
DOID	DOID:0061228
ICD-11	984450655
SNOMED CT	703219008
UMLS	C1838577
MedGen	325051
GARD	0010424
NORD	888
Is cancer (heuristic)	no

Also known as: CARASIL · cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy · cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy · cerebrovascular disease with thin skin, alopecia, and disc disease · Maeda syndrome

Data availability: 34 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › cerebral arteriopathy with subcortical infarcts and leukoencephalopathy › cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 2 › CARASIL syndrome

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

34 retrieved; paginated sample, class counts are floors:

8 uncertain significance, 6 pathogenic/likely pathogenic, 5 conflicting classifications of pathogenicity, 5 pathogenic, 5 benign/likely benign, 2 benign, 2 likely pathogenic, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
424706	NM_002775.4(HTRA1):c.[126delG];[961G>A]		Pathogenic	no assertion criteria provided
1332825	NM_002775.5(HTRA1):c.905G>A (p.Arg302Gln)	HTRA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
156099	NM_002775.5(HTRA1):c.821G>A (p.Arg274Gln)	HTRA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
180747	NM_002775.5(HTRA1):c.126del (p.Glu42fs)	HTRA1	Pathogenic	no assertion criteria provided
30244	NM_002775.5(HTRA1):c.883G>A (p.Gly295Arg)	HTRA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3049420	NM_002775.5(HTRA1):c.1156C>T (p.Arg386Ter)	HTRA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
560164	NM_002775.5(HTRA1):c.614C>G (p.Ser205Cys)	HTRA1	Pathogenic	criteria provided, single submitter
7487	NM_002775.5(HTRA1):c.1108C>T (p.Arg370Ter)	HTRA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
7488	NM_002775.5(HTRA1):c.904C>T (p.Arg302Ter)	HTRA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
7489	NM_002775.5(HTRA1):c.889G>A (p.Val297Met)	HTRA1	Pathogenic	criteria provided, single submitter
7490	NM_002775.5(HTRA1):c.754G>A (p.Ala252Thr)	HTRA1	Pathogenic	criteria provided, single submitter
1910224	NM_002775.5(HTRA1):c.497G>A (p.Arg166His)	HTRA1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
978704	NM_002775.5(HTRA1):c.235C>T (p.Gln79Ter)	HTRA1	Likely pathogenic	no assertion criteria provided
1331097	NM_002775.5(HTRA1):c.1274C>T (p.Ala425Val)	HTRA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
156100	NM_002775.5(HTRA1):c.854C>T (p.Pro285Leu)	HTRA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3907466	NM_002775.5(HTRA1):c.472G>C (p.Gly158Arg)	HTRA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
444239	NM_002775.5(HTRA1):c.589C>T (p.Arg197Ter)	HTRA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
870484	NM_002775.5(HTRA1):c.660C>G (p.His220Gln)	HTRA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1501480	NM_002775.5(HTRA1):c.820C>T (p.Arg274Trp)	HTRA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1507098	NM_002775.5(HTRA1):c.599C>T (p.Pro200Leu)	HTRA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
180746	NM_002775.5(HTRA1):c.961G>A (p.Ala321Thr)	HTRA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3779744	NM_002775.5(HTRA1):c.941T>C (p.Met314Thr)	HTRA1	Uncertain significance	criteria provided, single submitter
3779745	NM_002775.5(HTRA1):c.33_34insTC (p.Leu12fs)	HTRA1	Uncertain significance	criteria provided, single submitter
3779746	NM_002775.5(HTRA1):c.35dup (p.Leu13fs)	HTRA1	Uncertain significance	criteria provided, single submitter
871447	NM_002775.5(HTRA1):c.451C>A (p.Gln151Lys)	HTRA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
877269	NM_002775.5(HTRA1):c.1333G>A (p.Ala445Thr)	HTRA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1259856	NM_002775.5(HTRA1):c.1275-36C>T	HTRA1	Benign	criteria provided, multiple submitters, no conflicts
21324	NM_002775.5(HTRA1):c.102C>T (p.Ala34=)	HTRA1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
21325	NM_002775.5(HTRA1):c.108G>C (p.Gly36=)	HTRA1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
21326	NM_002775.5(HTRA1):c.108G>T (p.Gly36=)	HTRA1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 4 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
HTRA1	Definitive	Autosomal recessive	CARASIL syndrome	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HTRA1	Orphanet:199354	Cerebral autosomal recessive arteriopathy-subcortical infarcts-leukoencephalopathy
HTRA1	Orphanet:252128	Malignant peripheral nerve sheath tumor with perineurial differentiation
HTRA1	Orphanet:252212	Malignant triton tumor
HTRA1	Orphanet:482077	HTRA1-related autosomal dominant cerebral small vessel disease

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
HTRA1	HGNC:9476	ENSG00000166033	Q92743	Serine protease HTRA1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HTRA1	Serine protease HTRA1	Serine protease with a variety of targets, including extracellular matrix proteins such as fibronectin.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Protease	1	36.6×	0.027

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HTRA1	Protease	yes	3.4.21.107	IGFBP-like, PDZ, Peptidase_S1C

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
metanephric glomerulus	1
renal glomerulus	1
tendon of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HTRA1	287	ubiquitous	marker	tendon of biceps brachii, renal glomerulus, metanephric glomerulus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HTRA1	2,843

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HTRA1	Q92743	18

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Degradation of the extracellular matrix	1	117.7×	0.008	HTRA1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
chorionic trophoblast cell differentiation	1	2808.7×	0.002	HTRA1
programmed cell death	1	1296.3×	0.003	HTRA1
placenta development	1	443.5×	0.005	HTRA1
negative regulation of BMP signaling pathway	1	290.6×	0.006	HTRA1
negative regulation of transforming growth factor beta receptor signaling pathway	1	173.7×	0.008	HTRA1
positive regulation of apoptotic process	1	56.7×	0.021	HTRA1
proteolysis	1	34.2×	0.029	HTRA1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HTRA1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
HTRA1	28	Binding:28

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
HTRA1	3.4.21.107, 3.4.21.108	peptidase Do, HtrA2 peptidase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	HTRA1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
HTRA1	28	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.